14α,17α-ethanoestratrienes

ABSTRACT

##STR1## New 14α,17α-ethano-estratrienes of general formula (I) wherein R 1  is a hydrogen atom, an alkyl or acyl group with 1 to 12 carbon atoms, R 2  is a hydrogen atom or a methyl group, R 3  is a hydrogen atom or an acyl group with 1 to 12 carbon atoms and (a) is either (II) or (III), where R 4  is an alkyl residue in the α or β position with 1 to 8 carbon atoms or an α,β-alkenyl residue which may contain several double bonds or an α,β-alkinyl residue, both with 2 to 8 carbon atoms, are described. Also described is a process for producing them. These new compounds have a marked oestrogenic activity.

This invention relates to 14alpha,17alpha-ethanoestratrienes of generalformula I ##STR2## in which

R¹ means a hydrogen atom, an alkyl or acyl group with 1 to 12 carbonatoms,

R² means a hydrogen atom or a methyl group,

R³ means a hydrogen atom or an acyl group with 1 to 12 carbon atoms and##STR3## and R⁴ is an alpha- or beta-position alkyl radical with 1 to 8carbon atoms or an alpha,beta-alkenyl radical or an alpha,beta-alkinylradical, optionally exhibiting several double bonds, both radicals with2 to 8 carbon atoms.

Further, the invention relates to a process for the production ofcompounds of general formula I, pharmaceutical preparations, whichcontain compounds of general formula I as well as the use of thecompounds according to the invention for fertility control of women aswell as for treatment of estrogen deficiency symptoms of women.

As acyl groups R¹ and R³, radicals of organic carboxylic acids with 1 to12 carbon atoms are suitable. They are derived from aliphatic,cycloaliphatic, aliphatic-cycloaliphatic, cycloaliphatic-aliphatic andaromatic and aromatic-aliphatic monocarboxylic acids, preferably thoseacids that are derived from hydrocarbons. The number of carbon atoms inthe cycloaliphatics varies from 3 to 7, the phenyl as well as thenaphthyl radical can be mentioned as aromatics.

As radicals R¹ and R³ for the acyl groups the acetic, propionic,butyric, isobutyric, pivalic, caproic, acrylic, crotonic, heptylic,caprylic, pelargonic, decanoic, undecanoic, dodecanoic,3-cyclopentylpropionic and benzoic acid are preferred.

If R¹ stands for an alkyl group, in this case alkyl radicals, optionallywith one or more unsaturations, with 1 to 12 carbon atoms are suitable.R¹ can thus be an alkyl, alkenyl or alkinyl radical with up to 12 carbonatoms. Especially to be mentioned are all alkyl radicals correspondingto the acyl groups mentioned for R¹ and R³. The methyl group isespecially preferred.

A hydrogen atom is the preferred radical for R².

For the fragment ##STR4## there can stand either a C15-C16 double bondor C15-C16 alkylene group ##STR5## which is substituted in the 16position with an alpha- or beta-position alkyl radical or an optionallyrepeatedly unsaturated alk-1,2-enyl radical with 1 to 8 or 2 to 8 carbonatoms. They are especially the methyl, ethyl, propyl, isopropyl,propenyl, butyl, t-butyl, butadienyl, cyclopentylmethyl andcyclopentylmethylene as well as the hexyl group, of which the methylgroup can be mentioned as preferred.

Finally a straight-chain alk-1,2-inyl group with 2 to 8 carbon atoms issuitable as substituent R⁴. The ethinyl and propionyl group arepreferred.

14alpha,17alpha-etheno-bridged steroids are described in J. Chem. Soc.,Chex. Commun., 1986, 451-453 and 14alpha,17alphaetheno-bridged and14alpha,17alpha-ethano-bridged steriods in international patentapplication PCT/DE87/00361 as the compounds coming closest &o thecompounds of the general formula I, with the same substituents in 3 and17 position as the compounds according to the invention; in 13 positionthe known compounds exhibit a methyl group. While the compounds ofgeneral formula I present here exhibit the C15-C16 double bond or thealkyl radical on the C-16 atox in the upper ring of the steroidskeleton, the C15-C16 double bond or the C-16 alkyl substituent in/onthe lower D ring of the steroid skeleton is in the same arrangement (ineach base beta) of the 17 OR substituent (R=H, acyl). In other words,with the present compounds of formula I14alpha,17alphaethanoestratrienes (A) or14alpha,17alpha-ethano-16-alkylestratrienes (B) are involved, while withthe already known compounds 14alpha,17alpha-ethenoestratrienes (C) or14alpha,17alpha-alkylethano estratrienes (D) are involved: ##STR6##

Further, from PCT/DE87/00361 it comes out that the14alpha,17alpha-ethenoestratrienes of type C can be hydrogenated to thealso strongly estrogen-effective corresponding 15,16-dihydro compounds.

Like the compounds belonging to the prior art, the compounds accordingto the invention are distinguished by an extraordinarily strongestrogenic effectiveness. In the Allen-Doisy test after subcutaneousadministration they are as strongly estrogenically effective asethinylestradiol and of comparable effectiveness as the already knowncompounds of type (C).

In the Allen-Doisy test, an evaluation of vaginal smears inovariectomized rats is performed on days 3, 4, 5 and 8 after the singleadministration of the test substance. The following cycle stages aredistinguished:

1=diestrus (leukocytes and nucleated epithelial cells),

2=proestrus (nucleated epithelial cells),

3=estrus (denucleated horny plaques),

4=metestrus (denucleated horny plaques, leukocytes, epithelial cells).

After oral or subcutaneous administration, estrogenically effectivesubstances result in the proliferation of the vaginal epithelium and inthe cornification of surface cell layers. That amount of an estrogen isconsidered as a threshold value, at which 50% of the animals reach stage3.

The results of the Allen-Doisy test with14alpha,17alphaethano-1,3,5(10),15-estratetraene-3,17beta -diol as testcompound as well as14alpha,17alpha-ethano-1,3,5(10)estratriene-3,17beta-diol and estradiolas comparison compounds are summarized in table 1. The uterus weightsare determined after autopsy of those animals on which vaginal smearshad previously been made.

                                      TABLE 1                                     __________________________________________________________________________    Vaginal smear test according to Allen and Doisy (A 1.1 modified) on rats      with s.c. administration.                                                     Injection: 1× on d1; autopsy d5, n = 6/group: control n = 12                              Difference                                                                    body weight                                                                          Uterus weight   Uterus weight (mg)/100 g                                                                      Smears                                 d5 - d1 (g)                                                                          (moist).sup.1)                                                                        (dry).sup.1)                                                                          (moist) (dry)   n = pos./            Treatment         Mean                                                                              SD Mean                                                                              SD  Mean                                                                              SD  Mean                                                                              SD  Mean                                                                              SD  n                    __________________________________________________________________________                                                             = trt.               14alpha,17alpha-ethano-                                                                    /3,00 ug                                                                           -0.33                                                                             3.56                                                                             713.92                                                                            368.43                                                                            135.83                                                                            54.62                                                                             335.57                                                                            156.29                                                                            64.61                                                                             23.10                                                                             6/6                  1,3,5(10),15-estratetraene-                                                                /1,00 ug                                                                            6.50                                                                             2.59                                                                             415.62                                                                            250.80                                                                            77.23                                                                             37.73                                                                             199.21                                                                            129.50                                                                            36.92                                                                             19.64                                                                             6/6                  3,17beta-diol                                                                              /0,30 ug                                                                           11.50                                                                             2.26                                                                             238.45                                                                            25.65                                                                             44.93                                                                             3.84                                                                              110.19                                                                            14.62                                                                             20.74                                                                             2.21                                                                              6/6                               /0,10 ug                                                                           16.50                                                                             6.98                                                                             156.62                                                                            10.85                                                                             29.23                                                                             2.76                                                                               70.72                                                                             6.58                                                                             13.22                                                                             1.70                                                                              6/6                               /0,03 ug                                                                           18.17                                                                             4.75                                                                             128.07                                                                            17.22                                                                             25.38                                                                             5.28                                                                               58.89                                                                             6.68                                                                             11.65                                                                             2.17                                                                              0/6                  14alpha,17alpha-ethano-                                                                    /3,00 ug                                                                            0.67                                                                             6.86                                                                             576.37                                                                            248.15                                                                            92.98                                                                             21.53                                                                             276.18                                                                            113.26                                                                            44.81                                                                             10.05                                                                             6/6                  1,3,5(10)-estratrien-                                                                      /1,00 ug                                                                            2.83                                                                             4.83                                                                             327.72                                                                            37.87                                                                             66.87                                                                             13.52                                                                             158.32                                                                            23.83                                                                             32.38                                                                             7.77                                                                              6/6                  3,17beta-diol                                                                              /0,30 ug                                                                           11.33                                                                             3.56                                                                             299.50                                                                            71.34                                                                             45.72                                                                             6.04                                                                              135.06                                                                            34.94                                                                             20.50                                                                             2.28                                                                              6/6                               /0,10 ug                                                                           10.83                                                                             2.79                                                                             191.80                                                                            105.71                                                                            28.18                                                                             5.62                                                                               89.92                                                                            51.58                                                                             13.14                                                                             2.58                                                                              5/6                               /0,03 ug                                                                           17.33                                                                             3.72                                                                             134.80                                                                            41.83                                                                             24.18                                                                             3.13                                                                               60.90                                                                            22.05                                                                             10.83                                                                             1.51                                                                              2/6                  estradiol    /3,00 ug                                                                            7.67                                                                             5.28                                                                             367.28                                                                            108.65                                                                            71.65                                                                             14.70                                                                             170.30                                                                            49.06                                                                             33.38                                                                             7.18                                                                              6/5                               /1,00 ug                                                                            5.17                                                                             2.23                                                                             234.77                                                                            21.88                                                                             59.55                                                                             19.30                                                                             111.65                                                                             9.93                                                                             28.42                                                                             9.49                                                                              6/6                               /0,30 ug                                                                           12.00                                                                             2.10                                                                             192.10                                                                            40.03                                                                             42.18                                                                             17.18                                                                              89.32                                                                            18.90                                                                             19.57                                                                             8.01                                                                              6/6                               /0,10 ug                                                                           14.33                                                                             3.56                                                                             137.05                                                                            17.94                                                                             25.07                                                                             3.50                                                                               61.85                                                                             9.30                                                                             11.27                                                                             1.44                                                                              6/6                               /0,03 ug                                                                           20.17                                                                             4.75                                                                             123.17                                                                            13.29                                                                             23.60                                                                             4.98                                                                               54.85                                                                             5.67                                                                             10.52                                                                             2.32                                                                              0/6                  Control           21.08                                                                             4.25                                                                             123.72                                                                            20.19                                                                             27.58                                                                             6.09                                                                               54.20                                                                            11.27                                                                             12.09                                                                             3.11                                                                               0/12                __________________________________________________________________________     (M ± SD  p less than 0.05 vs. control, LSD  test)                          As other compounds,                                                           14alpha,17alphaethano-1,3,5(10)-estratriene-16alpha-ethinyl-3,17beta-diol     was tested; at a dose of 0.3 micrograms/d s.c. all 6 examined animals sho     positive smears.                                                         

It is surprising that the compounds according to the invention, whichcontain no 17alpha-ethinyl group, are at least as effective asethinylestradiol. Ethinylestradiol is still the most often used estrogenin oral treatment.

In comparison with ethinylestradiol, the compounds according to theinvention offer the advantage that they exhibit no 17betahydroxy group,which could cause undesirable metabolic reactions.

As is still to be explained, moreover they can be produced by asubstantially simpler process than the structurally close compounds oftype (C).

Thus, the invention also relates to compounds of general formula I foruse in the treatment of estrogen deficiency symptoms and for fertilitycontrol in women.

The compounds according to the invention can be formulated and used inthe same way as ethinylestradiol. They are processed according tomethods known in the art into the usual pharmaceutical agent forms withthe additives, vehicles and/or taste corrigents usual in galenicpharmacy. For oral administration, tablets, coated tablets, capsules,pills, suspensions or solutions are especially suitable. For parenteraladministration, oily solutions, such as, for example, sesame oil orcastor oil solutions, are especially suitable, which can optionallycontain in addition another diluent, such as, for example, benzylbenzoate or benzyl alcohol.

The active ingredient concentration in the pharmaceutical compositionsis dependent on the form of administration and the field of use. Thus,for example, for the treatment of estrogen deficiency symptoms, capsulesor tablets can contain 0.001 to 0.05 mg of active ingredient, oilysolutions for intramuscular injection per 1 ml approximately 0.01 to 0.1mg of active ingredient and vaginal ointments about 0.1 to 10 mg per 100ml of ointment. For contraception in women, the estrogens according tothe invention can be used in combination with gestagens. Tablets orcoated tablets for daily intake of a tablet or a coated tablet are tocontain preferably 0.003 to 0.05 mg of the estrogen according to theinvention and 0.05 to 0.5 mg of a gestagen.

The compounds according to the invention can be used in the case ofestrogen deficiency symptoms of women, such as, for example, amenorrhea,dysmenorrhea, sterility, frigidity, endometritis, colpitis andmenopausal symptoms. Further, the compounds can be used as estrogeniccomponents in compound preparations with gestagens for fertility controlin women.

The new compounds of general formula I ##STR7## in which R¹, R² and R³and ##STR8## have the meaning already indicated, are produced so that##STR9## a compound of general formula IIIa ##STR10## in which

R² has the meaning indicated in formula I is first hydrogenated and thendecarboxylated and oxidized to a compound of general formula II'a##STR11## meaning a methyl group,

a compound of general formula IIIb ##STR12## in which R² has the meaningalready indicated, is reduced to a compound of general formula II'b##STR13## an alkyl radical or an alpha,beta-alkenyl radical, both with 2to 8 carbon atoms, optionally exhibiting several double bonds

a compound of general formula IIIc ##STR14## in which R² has the meaningalready indicated, is reacted with an appropriate Wittig reagent to acompound of general formula II"c ##STR15## in which R^(4c") representsan alpha,beta-alkenyl radical, with 2-8 carbon atoms, optionallyexhibiting several double bonds

the compound of general formula II"c optionally is hydrogenated to acompound of general formula II'c ##STR16## in which R^(4c') representsan alkyl radical with 2 to 8 carbon atoms, ##STR17## meaning analpha,beta-alkinyl radical with 2 to 8 carbon atoms, a compound ofgeneral formula III c ##STR18## is reacted in a modified Wittig reactionwith a mixture of triphenylphosphane and tetrahalomethane CHal₄, and Halcan be bromine and iodine, preferably bromine, to a compound of generalformula II''d ##STR19## and then in a compound of one of generalformulas II'a, II'b, II"c, II'c or II"d optionally the 3-methyl ether iscleaved and if the process variant d) is present, after conversion ofthe compound of general formula II"d or the corresponding 3-hydroxycompound by cleavage of HHal with a base and halogen/hydrogen exchangeand optionally after coupling of the resulting H-ethinyl compound with alinear alkylation reagent exhibiting 1 to 6 carbon atoms to a compoundof general formula II'd ##STR20## in which R^(4d) has the meaningalready indicated and then optionally the released 3-hydroxy group isagain etherified and/or the 17-acetoxy group is saponified, optionallythe 3-and 17-hydroxy groups are again esterified and optionally a3,17-diacyloxy compound thus obtained is selectively saponified to the3-hydroxy-17-acyloxy compound.

Depending on which intermediate or end product of general formulas II'a,II'b, II"c, II'c or II"d (the compounds of these formulas can also beend products of general formula I, if R¹ is to be a methyl group and R³is to be an acetyl group) is desired, different procedures according tothe invention are necessary.

a) The D ring is to exhibit a C15-C16 double bond: starting from a16alpha-carbaldehyde of general formula IVa ##STR21## in which R² standsfor an H atom or a methyl group, by oxidation of the carbonyl group, forexample with Jones reagent (chromium(VI) oxide/sulfuric acid), thecorresponding carboxyl group IIIa is produced. ##STR22## Byhydrogenation of the 14alpha,17alpha-etheno bridge, decarboxylation andoxidation (introduction of the C15-C16 double bond) IIIa is convertedinto a compound of general formula II'a. ##STR23## The decarboxylationand oxidation are performed by heating in a solvent under the action ofat least one oxidation agent, for example with lead tetraacetate andcopper(II) acetate hydrate in benzene or toluene.

b) The D ring is to have a C-16 alpha- or beta-methyl group:

a compound of general formula IIIc ##STR24## in which R² stands for an Hatom or a methyl group and the aldehyde function can be in the alpha orbeta position, by reaction with 1,2-dimercaptoethane is converted in itsethylene-1,2-dithioketal derivative IIIb; ##STR25## this compound offormula IIIb is then reduced with a protic solvent to a compound ofgeneral formula II'b ##STR26## for example, with Raney nickel inalcohol.

c) The D ring is to carry a C16-alpha or beta-alkyl or C-16alpha orbeta-alkenyl radical, with 2 to 8 carbon atoms, optionally exhibitingseveral double bonds:

also starting from an aldehyde of general formula IIIc by a C--C linkagereaction the 16alpha or 16beta-alkenyl or alkyl side chain issynthesized, for example, by Wittig reaction of IIIc with a suitableWittig reagent, i.e., with a Wittig reagent poorer by one C atom thanR^(4c").

The double bond resulting in the C16 side chain by the Wittig reaction(as well as optionally present in other double bonds) can optionally beagain eliminated by hydrogenation.

By the variant described under c) there are achieved both compounds ofgeneral formula II"C ##STR27## in which R^(4c) " represents at least onesimply unsaturated alkenyl radical with 2 to 8 carbon atoms andcompounds of general formula II'c ##STR28## in which now in R^(4c') thedouble bonds which were present in R^(4c") are hydrogenated.

d) The D ring is to exhibit a straight-chain C16 alpha- or C16beta-alk-1,2-inyl radical with 2 to 8 carbon atoms as substituent:

An aldehyde of formula IIIc as starting product is reacted in a modifiedWittig reaction with a mixture of triphenylphosphine andtetrabromomethane or tetraiodomethane. In this case, triphenyl-dibromo(or diiodo) methylene phosphorane functions as reactive species. Thenhydrogen bromide or hydrogen iodide is then eliminated from theresulting Wittig reaction product of general formula II"d with a base,such as, for example, n-butyllithium. In the aqueous working up of thereaction product obtained after the elimination, the corresponding 16alpha- or 16 beta-ethinyl compound is obtained; if afterdehydrohalogenation an n-alkylation reagent with 1 to 6 carbon atoms inthe alkyl radical is added, compounds of general formula II'd areachieved, in which R⁴ is an alpha- or beta-position alk-1,2-inyl radicalwith 3 to 8 carbon atoms. Thus, for example, working up in the presenceof methyl iodide leads to the corresponding 16-prop-1,2-inyl compound.

This invention also relates to the compounds of formula IV ##STR29## inwhich

R² stands for a hydrogen atom or a methyl group and either

X means an alpha-position carbaldehyde group ##STR30## and

A-B means a C--C single bond as well as E-F means a C--C double bond orC--C single bond,

or

X means a beta-position carbaldehyde group ##STR31## and A-B and E-Fmean two C--C double bonds or two single bonds, since these compoundsrepresent valuable and variously usable intermediate products because ofthe chemically versatile keto group.

The production of the compounds of general formula IV takes placestarting from 3-methoxy-1,3,5(10),14,16-estrapentaen-17-yl acetate (R²=H) ##STR32## [G. H. Rasmusson et al., Steroids 22, 107, (1973)] orstarting from 3-methoxy-1,3,5(10),14,16-estrapentaene-18-methyl-17-ylacetate (R² =CH₃) by reaction with an unsaturated aldehyde in vicinalposition to the keto group. Instructions for preparation of thelast-named compound are found in example 16. For example, reaction ofthe first compound (R² =H) with acrolein in the cold and in the presenceof a Lewis acid yields the [4+2] cyclo adduct with alpha-positionaldehyde function the C16 atom while the [4+2] cyclo adduct withbeta-position aldehyde function on the on ##STR33## the C16 atom isformed with propinal in the heat. Both cyclo adducts can becatalytically hydrogenated, for example with palladium-activated carbon(also if R² =CH₃).

Thus the compounds of general formula I according to the invention aredistinguished especially by their high estrogenic effectiveness, andthey can in addition be produced according to a relatively simpleprocess and easily by the compounds of general formula IVa or IIIc.

The known 14alpha,17alpha-etheno-1,3,5(10)-estratrienes (C) so far havebeen produced by reduction of the corresponding 16-phenyl sulfones offormula ##STR34## in which

R^(1a) =R¹ and R^(3a) =R³ or mean precursors of R¹ or R³, with an excessof 6% sodium amalgam (J. Chem. Soc.., Chem. Commun. 1986,451-453). Forexample, for reductive elimination of the phenyl sulfone groups from 2 gof 14alpha,17alpha-etheno-3-methoxy-16alpha-phenylsulfonyl-1,3,5(10)-estratrien-17beta-ol acetate in the usual way 31.5 g of 6% sodiumamalgam is necessary, which contains almost 30 g of mercury. For reasonsof economy and because of the extreme toxicity of the mercury, such asynthesis cannot be transferred on a reasonable technical scale, since,for example, to reduce 100 kg of the above-named sulfone, 1.5 tons ofmercury would be necessary. On the other hand, the present processavoids these disadvantages and damages that occur in dealing withmercury.

Moreover, the compounds of general formula I according to the invention,in which ##STR35## stands for a C15-C16 double bond, as shown in example15, can be hydrogenated, by which identical 15,16-dihydro compounds areachieved as by hydrogenation of the known14alpha,17alpha-ethenoestratrienes of type.C.

This invention is explained in greater detail by the following examples.

EXAMPLE 117beta-Acetoxy-14alpha,17alpha-etheno-3-methoxy-1,3,5(10)-estratriene-16alpha-carbaldhyde(2)

10.0 g (30.8 mmol) of 3-methoxy-1,3,5(10),14,16-estra-pentaen-17-ylacetate (1) [G. H. Rasmusson et al., Steroids 22, 107, (1973)] and 4.17ml (62.7 mmol) of acrolein in 124 ml of toluene were mixed byinstillation with ice cooling with 0.19 ml (1.6 mmol) of borontrifluoride etherate in 11.4 ml of toluene. The reaction was stirred for16 hours at room temperature and then poured onto ice/water. Then it wasextracted with ethyl acetate and the organic phase, after washing withsodium bicarbonate solution and water, was dried on sodium sulfate.Filtration and evaporation of the solvent yielded 9.9 g of solidresidue. By chromatography on silica gel with ethyl acetate/hexane(1:2→1:1), 8.55 g of (2) with a melting point of 183-185° C. wasobtained.

[α]²⁰ D+102.5° (C. 0.120, CHCl₃)

EXAMPLE 217beta-Acetoxy-14alpha,17alpha-etheno-3-methoxy-1,3,5(10)-estratariene-16alpha-carboxylicacid (3)

8.0 g (21.0 mmol) of 2 in 180 ml of acetone was mixed by instillationwith 11.0 ml (29.3 mmol) of Jones reagents (2.67 g of chromium(VI) oxidein 7.7 ml of water and 2.3 ml conc. sulfuric acid) at 0° C. The reactionmixture was stirred for 3 1/2 hours with ice cooling and 1 hour at roomtemperature and then poured onto ice/water. Then it was extracted withethyl acetate, the organic phase was washed with water and dried onsodium sulfate. Filtration and removal of solvent yielded 8.03 g of (3)with a melting point of 194-198° C.

EXAMPLE 317beta-Acetoxy-14alpha,17alpha-ethano-3-methoxy-1,3,5(10)-estratriene-16alpha-carboxylicacid (4)

8.0 g of (3) was hydrogenated in 672 ml of ethanol in the presence of1.76 g of Pd-C (10%) at standard pressure. After filtration andevaporation of the solvent, 7.5 g of (4) was obtained as crude productwith a melting point of 224-227° C.

EXAMPLE 414alpha,17alpha-Ethano-3-methoxy-1,3,5(10),15-estratetraen-17beta-olacetate (5)

7.45 g (18.7 mmol) of (4) and 0.65 (3.26 mmol) of copper(II) acetatehydrate were stirred in 1.5 ml of pyridine and 137 ml of benzene firstfor 30 minutes at room temperature and after addition of 13.5 g (30.4mmol) of lead tetraacetate at 90° C. were stirred for 4 hours in anitrogen atmosphere with exclusion of light. The reaction mixture wasfiltered through silica gel, rewashed with 2 liters of ethylacetate/hexane (1:1) and the filtrate was concentrated by evaporation.By chromatography of the oily residue on silica gel with ethylacetate/hexane (1:1), 1.27 g of (5) was obtained as bright yellow oil,additionally 1.16 g was contaminated.

EXAMPLE 514alpha,17alpha-Ethano-1,3,5(10),15-estratetraene-3,17beta-diol (6)

1.18 g (3.35 mmol) of (5) in 354 ml of toluene was refluxed with 88.5 ml(106.2 mmol) of diisobutylaluminium hydride (1.2 molar in toluene) for14 hours in a nitrogen atmosphere. The cooled reaction mixture waspoured on ice/dilute acetic acid. Then it was extracted with ethylacetate and the organic phase, after washing with sodium bicarbonatesolution and water, was dried on sodium sulfate. After filtration andevaporation of the solvent, 1.3 g of solid was obtained, which afterchromatography on silica gel with hexane--hexane/ethyl acetate (1:1)yielded 540 mg of (6) with a melting point of 200° C.

[α]²⁰ D-11.4° (C 0.105 CHCl₃).

EXAMPLE 617beta-Acetoxy-14aloha,17aloha-ethano-3-methoxy-1,3,5(10)-estratriene-16alpha-carbaldhyde(7)

2.0 g of (2) in 250 ml of ethyl acetate was hydrogenated with 0.5 g ofPd-C (10%) at standard pressure. After removal of the catalyst andevaporation of the solvent, 1.99 g of (7) with a melting point of151-152° C. was obtained.

EXAMPLE 716alpha-(1,3-Dithiolan-2-yl)-14aloha,17alohaethano-3-methoxy-1,3,5(10)-estratrien-17beta-ol acetate (8)

6.51 g (17.0 mmol) of (7) and 2.26 ml (26.9 mmol) of1,2-dimercaptoethane were dissolved in 15 ml of methylene chloride andmixed with instillation at 0°0 C. with 0.6 ml (4.76 mmol) of borontrifluoride etherate in 5.9 ml of methylene chloride at 0° C. Thereaction mixture was stirred for 3 more hours at room temperature,diluted with ethyl acetate and washed with 5% sodium hydroxide solutionand water. Drying of the organic phase on sodium sulfate, filtration andevaporation of the solvent yielded 7.62 g of crude product of (8), whichis used for Raney nickel desulfurization.

EXAMPLE 814aloha,17alpha-Ethano-3-methoxy-1,3,5(10)-estratriene-16alphamethyl-17beta-olacetate (9)

7.52 g of (8) was refluxed in 400 ml of ethanol together with about 15 gof Raney nickel in a nitrogen atmosphere. After filtration and removalof the solvent 5.60 g of (9) with a melting point of 115° C. wasobtained.

EXAMPLE 914alpha,17alpha-Ethano-16aloha-methyl-1.3.5(10)-estratriene3,17beta-diol(10)

2.0 g (5.42 mmol) of (9) was refluxed with 75.0 ml (91.4 mmol) ofdiisobutylaluminum hydride (1.2 molar in toluene) for 5 1/2 hours undernitrogen. The cooled reaction mixture was diluted with toluene andpoured onto ice/dilute acetic acid. After addition of common salt, itwas extracted with ethyl acetate and the organic phase was washed withsodium bicarbonate solution and water. After drying on sodium sulfate,filtration and after removal of the solvent, 1.71 g of solid wasobtained. Recrystallization in acetone/hexane yielded 610 mg of (10)with a melting point of 264-265° C.

[α]²⁰ D+30.4° (C 0.105; CHCl₃).

EXAMPLE 1017beta-Acetoxy-14aloha,17aloha-etheno-3-methoxy-1.3.5(10),15-estratetraene-16-carbaldhyde(11)

10.0 g (30.8 mmol) of (1) and 28.21 g of a mixture of propinal,2-butanone and diethyl ether [produced according to M.G. Valiev et. al.Synthesis 461 (1960); batch:36.5 g (0.65 mmol) of propargyl alcohol; theproduct after working up according to instructions still contains2-butanone and diethyl ether] in 114 ml of toluene were refluxed for 10hours. The cooled reaction mixture was concentrated by evaporation(15.57 g of crystallizing oil) and recrystallized in ethylacetate/hexane. 7.84 g of (11) with a melting point of 155.5° C. wasobtained.

[α]²⁰ D-52.3° (C 0.105; CHCl₃).

EXAMPLE 1117beta-Acetoxy-14alpha,17alpha-ethano-3-methoxy-1,3,5(10)-estratriene-16beta-carbaldhyde (12)

2.0 g of (11) was hydrogenated with 400 mg of Pd-C (10%) in 40 ml ofethyl acetate at standard pressure. After filtration and removal of thesolvent, 2.06 g of solid remained.. The crude product--according to ¹H-NMR consisting of 85% 16beta- and 15% 16alpha-carbaldhyde--is used forthioketalation.

EXAMPLE 1216beta-(1.3-Dithiolan-2-yl)-14aloha,17alpha-ethano-3-methoxy-1,3,5(10)-estratrien-17beta-ol acetate (13)

3.0 g (7.84 mmol) of (12) and 1.04 ml (12.4 mmol) of1,2-dimercaptoethane are dissolved in 7 ml of methylene chloride andmixed by instillation at 0° C. with 0.28 ml (2.20 mmol) of borontrifluoride etherate in 2.7 ml of methylene chloride. The reactionmixture was stirred for 20 minutes at 0° C. and 3 hours at roomtemperature. After dilution with ethyl acetate, the reaction mixture waswashed with 5% sodium hydroxide solution and water. The organic phasewas dried on sodium sulfate, filtered and evaporated to dryness. 3.06 gof (13) was obtained as crude product, which was used for Raney nickeldesulfurization.

EXAMPLE 1314alpha,17alpha-Ethano-3-methoxy-1,3,5(10)-estratriene-16beta-methyl-17beta-olacetate (14)

3.0 g of (13) was refluxed together with about 7.5 g of Raney nickel in200 ml of ethanol under protective gas. After cooling, filtration andevaporation of the solvent, 2.40 g of colorless oil was obtained, whichthen is reacted with diisobutylaluminum hydride.

EXAMPLE 1414alpha,17alpha-Ethano-16beta-methyl-1,3,5(10)-estratriene-3,17beta-diol(15)

2.22 g (6.02 mmol) of (14) was refluxed with 84.4 ml (101.2 mmol) ofdiisobutylaluminum hydride (1.2 molar in toluene) for 5 hours underinert gas. The reaction mixture was worked up analogously to (10). Afterdrying, 1.70 g of solid was obtained, which after chromatography onsilica gel with toluene → toluene/ethyl acetate (4:1) yielded 355 mg of(15) with a melting point of 233° C.

[α]²⁰ D+82.0° (C 0.1; CHCl₃).

EXAMPLE 15 14alpha,17alpha-Ethano-1,3,5(10)-estratriene-3,17beta-diol(16)

200 mg (0.675 mmol) of (6]in 25 ml of ethanol was hydrogenated in thepresence of 50 mg of Pd-C (10%) at standard pressure. After filtrationand evaporation of the solvent, 200 mg of (16) with a melting point of227-230° C. was obtained as crude product.

EXAMPLE 1617beta-Acetoxy-16aloha-(2,2-dibromovinyl)-14aloha,17aloha-ethano-3-methoxy-1,3,5(17)

18.9 g of carbon tetrabromide is added at -10° C. to 7.3 g of 7 and 30.0g of triphenylphosphine in 583 ml of methylene chloride. The reactionmixture is stirred for 2 more hours at -10° C. and then washed withsodium bicarbonate solution and water. The organic phase is dried onsodium sulfate, filtered and concentrated by evaporation. Filtration ofthe solid residue (46.3 g) with ethyl acetate/hexane (1:3) throughsilica gel yields 9.8 g of 17 as crystallizing oil.

EXAMPLE 1717beta-Acetoxy-16aloha-(2,2-dibromovinyl)-14alpha,17alpha-ethano-3-methoxy-1,3,5(10)-estratrien-3-ol(18)

38.1 ml of a 1 molar solution of boron tribromide in methylene chlorideis instilled at -35° C. in 9.5 g of 17 in 229 ml of methylene chloride.After 4 hours stirring at 0° C. the reaction mixture is mixed with icewater and with methylene chloride. The organic phase is washed withwater and dried on sodium sulfate. After filtration and removal of thesolvent, 9.2 g of 18 is obtained as bright yellow foam.

EXAMPLE 1816aloha-Ethinyl-14alpha,17aloha-ethano-1,3,5(10)-estratriene-3,17beta-diol(19)

4.0 g of 18 in 73 ml of tetrahydrofuran is mixed with instillation at-78° C. under nitrogen with 28.6 ml of a 1.6 molar solution ofbutyllithium in tetrahydrofuran. After 3.5 hours stirring at -78° C 100ml of saturated ammonium chloride solution is added to the reactionmixture. After heating to room temperature it is extracted with ethylacetate and the organic phase is washed with water. After drying onsodium sulfate, filtration and evaporation of the solvent, 3. g of solidaccumulates, which after chromatography on silica gel with ethylacetate/hexane (1:2) yields 1.4 g of solid. After recrystallization inisopropanol 380 mg of 19 with a melting point of 226-228° C. isobtained.

EXAMPLE 19 3-Methoxy-1,3,5(10),14,16-estra-pentaene-18-methyl-17-ylacetate

2.5 g of 18beta-ethyl-3-methoxygona-1,3,5(10),14-tetraen-17-one(produced according to US patent 3,577,410) and 1.0 g ofp-toluenesulfonic acid anhydride are refluxed in a mixture of 25 ml ofacetic anhydride and 25 ml of isopropenyl acetate for 8 hours. Forworking up, the reaction mixture obtained was poured into ice water andthen pyridine was added. It was stirred for 2 more hours, taken up inethyl acetate, washed neutral with sodium bicarbonate and common saltsolution and dried on sodium sulfate. Removal of the solvent in a vacuumyielded 2.4 g of crude product, whose further purification [HPLC,reversed phase, 600 ml column, eluent hexane/ethyl acetate (0→30% ethylacetate)] yielded 800 mg of the title compound with a melting point of120° C.

We claim:
 1. A 14α,17α-ethanoestratriene of formula I ##STR36## whereinR¹ is H or a C₁₋₁₂ -alkyl or -acyl group,R² is H or a methyl group, R³is H or a C₁₋₁₂ -acyl group, and ##STR37## is either ##STR38## whereinis an α- or β-position C₁₋₈ -alkyl radical or a C₂₋₈ -α,β-alkenylradical or a C₂₋₈ -α,β-alkinyl radical optionally having additionaldouble bonds.
 2. A compound of claim 2 whichis14α,17α-Ethano-1,3,5(10),15-estratetraene-3-17β-diol;14α,17α-ethano-16α-methyl-1,3,5(10)-estratriene-3,17.beta.-diol;14α,17α-ethano-16β-methyl-1,3,5(10)-estratriene-3,17β-diol;14α,17α-ethano-3-methoxy-1,3,5(10),15-estratetraen-17β-ol acetate;14α,17α-ethano-3-methoxy-1,3,5(10)-estratriene-16α-methyl-17β-olacetate;14α,17α-ethano-3-methoxy-1,3,5(10)-estratriene-16β-methyl-17β-olacetate; or16α-ethinyl-14α,17α-ethano-1,3,5(10)-estratriene-3,17.beta.-diol. 3.14α,17α-Ethano-1,3,5(10),15-estratetraene-3,17β-diol, a compound ofclaim
 1. 4. A pharmaceutical preparation comprising an effective amountof a compound of claim 1 and a pharmaceutically acceptable excipient. 5.A pharmaceutical preparation comprising an effective amount of acompound of claim 2 and a pharmaceutically acceptable excipient.
 6. Amethod of controlling fertility, comprising administering an effectiveamount of a compound of claim
 1. 7. A method of treating estrogendeficiency symptoms in a woman in need of such treatment, comprisingadministering an effective amount of a compound of claim 1.